Paracetamol-based pharmaceutical composition

ABSTRACT

The object of the invention is an ophthalmic composition containing between 0.1 to 10% by weight of paracetamol in an ophthalmic excipient.

The present invention relates to a paracetamol(n-acetyl-p-aminophenol)-based pharmaceutical composition.

Paracetamol is a compound well known for its antipyretic and analgesic activity.

This activity has been considered to be due to the inhibition of the synthesis of the prostallandins in the central nervous system. However, even though it inhibits the cyclo-oxygenase in the central nervous system, it shows no activity on this enzyme in the periphery (see, in particular, M. Scott Linscott, Clinical Therapeutics 9, 1, 1986).

Moreover, paracetamol has hitherto been administered, in practice, by the oral route.

The Applicant has made the surprising discovery that paracetamol administered to the eye has a useful pharmacological activity and may be used as an analgesic as well as for the treatment and prevention of cataracts.

Thus, the invention relates to an ophthalmic composition containing from 0.1 to 10% by weight of paracetamol in an ophthalmic excipient.

By ophthalmic excipient is meant an excipient which allows the administration of the active ingredient to the eye and which is not harmful to the eye. The composition may be made available in the form of an ophthalmic solution containing an aqueous solution, paracetamol and a buffer and, optionally, an antioxidant and a preservative.

The composition may also be constituted by an aqueous ophthalmic gel, an aqueous ophthalmic emulsion or an ophthalmic ointment.

Examples of ophthalmic compositions according to the invention will be given hereafter.

EXAMPLE 1 Collyrium Containing 1% Paracetamol

The following composition is prepared:

    ______________________________________                                         Paracetamol            1      g                                                Sodium metabisulfite   0.1    g                                                EDTA                   50     mg                                               Benzalkonium chloride  5      mg                                               NaH.sub.2 PO.sub.4, 2H.sub.2 O                                                                        0.38   g                                                Na.sub.2 HPO.sub.4, 10H.sub.2 O                                                                       1.6    g                                                NaCl                   0.16   g                                                Purified water qsp     100    ml                                               ______________________________________                                    

The composition has a pH between 6.8 and 7.2.

EXAMPLE 2 Ophthalmic Aerosol Containing Paracetamol

The composition of Example 1 may be packaged in an aerosol container.

EXAMPLE 3 Collyrium Containing 5% Paracetamol

The following composition is prepared:

    ______________________________________                                         Paracetamol            5      g                                                Sodium metabisulfite   0.1    g                                                Nipagine               26     mg                                               Nipasol                14     mg                                               NaH.sub.2 PO.sub.4, 2H.sub.2 O                                                                        0.38   g                                                Na.sub.2 HPO.sub.4, 10H.sub.2 O                                                                       1.6    g                                                Cremophore.sup.R       25     g                                                Water qsp              100    ml                                               ______________________________________                                    

EXAMPLE 4 Paracetamol-Based Ophthalmic Gel

1% carbopol is added to the composition of Example 1. The pH is adjusted to 7 with NaOH.

EXAMPLE 5 Paracetamol-Based Ophthalmic Ointment

The following composition is prepared:

    ______________________________________                                         Paracetamol        5 g                                                         Vaseline          50 g                                                         Viscous vaseline oil                                                                             15 g                                                         Lanolin           35 g                                                         ______________________________________                                    

EXAMPLE 6 Ophthalmic Emulsion

The following emulsion is prepared:

    ______________________________________                                         Paracetamol            1      g                                                Sodium metabisulfite   0.1    g                                                EDTA                   50     mg                                               Benzalkonium chloride  5      mg                                               NaH.sub.2 PO.sub.4, 2H.sub.2 O                                                                        0.38   g                                                Na.sub.2 HPO.sub.4, 10H.sub.2 O                                                                       1.6    g                                                NaCl                   0.16   g                                                Cremophore.sup.R       10     g                                                Fatty excipient        30     g                                                Water qsp              100    ml                                               ______________________________________                                    

Pharmacological results demonstrating the properties of the compositions according to the invention are given below.

I. Effect on Photokeratitis Induced by UV-B in the Rabbit

10 Male, albino New Zealand rabbits of means weight 2 kg and free of any ocular infection (prior ophthalmic examination) are used for the assays.

The irradiations were performed as follows:

50 μl of physiological serum were instilled into the left eye. The animals were placed in a restraining cage under UV light. The left eye was irradiated with UV-B (312 nm) (the right eye being protected) at an intensity of 0.4 J/day (which corresponds to 3'30" of exposure) for 7 days.

Macroscopic ocular examinations were made every day.

Criteria of evaluation applied:

redness and edema of the nictitating membrane and the palpebral and bulbar conjunctivae,

corneal opacity

neovascularization of the cornea.

Scoring scale used:

(1) Nictitating membrane and palebral and bulbar conjunctivae

very slight redness and edema 1

slight redness and edema 2

moderate redness and edema 3

quite considerable redness and edema 4

marked redness and edema 5

very marked redness and edema 6

(2) Degree of corneal opacity

presence of a diffuse translucent zone

presence of a readily identifiable translucent zone; iris clearly visible

presence of a slightly opalescent zone; iris discernible

presence of an opalescent zone; iris invisible.

(3) Neovascularization

presence of a few small vessels

presence of quite a number of small vessels

presence of many small vessels or a few large vessels

presence of very many small vessels or many large vessels

presence of very many large vessels.

Treatment

These animals were divided into 2 homogeneous groups of 5 animals (groups A and B) on the basis of the scores obtained after the last period of irradiation.

The treatment was started after the last period of irradiation: instillations of 25 μl of the collyrium under test (see Table I) in the left eye 4 times a day at intervals of 2 h S 30.

                  TABLE I                                                          ______________________________________                                                        Collyrium B                                                                              Collyrium A                                           ______________________________________                                         Paracetamol      1.000    g      --                                            Benzalkonium chloride                                                                           0.005    g      0.005  g                                      Sodium metabisulfite                                                                            0.100    g      0.100  g                                      Monosodium phosphate 2H.sub.2 O                                                                 0.380    g      0.380  g                                      Disodium phosphate 12H.sub.2 O                                                                  1.600    g      1.600  g                                      Sodium chloride  0.160    g      0.386  g                                      Purified water qsp                                                                              100.000  ml     100.000                                                                               ml                                     pH               6.81            6.77                                          ______________________________________                                    

Results

The results are presented in Table II and demonstrate an improvement of opacity and corneal neovascularization in the rabbits treated with the eye lotion B according to the invention, as from the 5th day of treatment.

                  TABLE II                                                         ______________________________________                                         Sums of the scores determined after observations                               of the rabbits in groups A and B                                                            bulbar   palpebral                                                nictitating  con-     con-           neovascul-                                membrane     junctiva junctiva opacity                                                                              arization                                 ______________________________________                                         1st day                                                                        Group A                                                                               28        25       28     13    13                                      Group B                                                                               30        28       39     14    13                                      3rd day                                                                        Group A                                                                               16        14       15     9     18                                      Group B                                                                               19        12       17     7     15                                      5th day                                                                        Group A                                                                               14        7         9     6     12                                      Group B                                                                               14        7        10     4     11                                      7th day                                                                        Group A                                                                               10        6         8     6      9                                      Group B                                                                                9        3         6     1      5                                      9th day                                                                        Group A                                                                                7        3         5     3      6                                      Group B                                                                                6        2         5     0      1                                      ______________________________________                                    

II- Effects on the Rupture of the Blood-Aqueous Barrier Induced by Paracentesis in the Rabbit

Paracentesis of the anterior chamber in the rabbit causes ocular inflammation characterized by various signs: hyperemia, myosis, increase in intraocular pressure and rupture of the blood-aqueous barrier.

This ocular traumatism also involves release of prostaglandins, in particular PGE2, into the aqueous humor. These endogenous prostaglandins play an important role in the rupture of the blood-aqueous barrier.

The experiments were performed on female New Zealand rabbits, of mean weight 2 kg and locally anesthetized by instillation of Cebesine^(R).

The primary aqueous humor (about 0.1 ml) was withdrawn from both eyes by puncture through the cornea into the anterior chamber while avoiding any contact of the needle with the anterior face of the iris and the crystalline lens.

A second paracentesis was performed SO minutes later after the animal had been sacrificed by means of pentobarbital sodium (120 mg/kg i.v.): the secondary aqueous humor thus obtained was diluted 1/2 with heparin in order to prevent coagulation due to fibrin.

The protein concentration in the aqueous humor was measured according to the method of Lowry et al. (J. Biol. Chem. 193, 265-275, 1951).

The animals were treated by instillation of 25 μl of the test solution into both eyes 20 and 10 mn before paracentesis.

The group of animals treated with a reference solution was included.

The formulae of the ophthalmic solutions are the following:

                  TABLE III                                                        ______________________________________                                         Composition                                                                                reference     3% paracetamol                                                   solution      solution                                             ______________________________________                                         Paracetamol                   0.300  g                                         PEG 400       5.000   g       5.000  g                                         Water qsp     10.000  ml      10.000 ML                                        ______________________________________                                    

The pretreatment by means of paracetamol in a 3% ophthalmic solution significantly inhibits protein extravasation and the increase in the level of PGE2 in the aqueous humor (Tables IV and V).

Paracetamol is classically described as a very weak inhibitor of PG synthetase, with the exception of that contained in cerebral tissue (Bowman W. C. and Rand J. J. "textbook of pharmacology", 2nd ed. Oxford, Blackwell, 1980).

In this ocular traumatic model, paracetamol does, however, inhibit the release of PGE2 into the aqueous humor by an unknown mechanism, and hence the rupture of the blood-aqueous barrier.

                  TABLE IV                                                         ______________________________________                                         Inhibition of the extravasation of protein induced by                          paracentesis after instillation of paracetamol                                             Proteins       Inhibition                                          Treatment   (mg/ml)        (%)      (n)                                        ______________________________________                                         Reference solution                                                                         34.3 +/- 9.3   --       (10)                                       3% Paracetamol                                                                             23.2 +/- 11.2  32        (9)                                       ______________________________________                                          n: number of measurements per group                                      

                  TABLE V                                                          ______________________________________                                         Inhibition of the increase in the level of PGE2 in                             the aqueous humor induced by paracentesis                                                    PGE2         Inhibition                                          Treatment     (mg/ml)      (%)      (n)                                        ______________________________________                                         Reference solution                                                                           4.8 +/- 1.3  --       (9)                                        3% Paracetamol                                                                               3.0 +/- 0.6  34       (7)                                        ______________________________________                                          n: number of measurements per group                                       

We claim:
 1. Method for the treatment of ocular pain or inflammation comprising topically administering a composition comprising 0.1-10% by weight of N-acetyl-p-aminophenol to the eye. 